The potential of amorphous solid dispersions to improve the solubility, dissolution rate and bioavailability of poorly water soluble drugs is well known. However, the number of formulations that have made it through to the market is limited because of the unstable nature of the amorphous form, which often results in recrystallization of the drug with the subsequent loss of the solubility and dissolution advantages. Thus, ensuring the stability constitutes a major challenge in the development of amorphous solid dispersions.

Background

The thermodynamic stability of a solid amorphous dispersion can only be ensured by molecularly dispersing (dissolving) the drug in the polymer below its saturation solubility. Therefore, the prediction of drug-polymer solubility at room temperature is of great academic and industrial interest. By assuming that a drug behaves as a solvent for an amorphous polymer it is possible to describe the solubility of a drug in a polymer using the Flory-Huggins model:

where $\Delta H_m$ and $T_m$ are the enthalpy of fusion and melting temperature for the pure drug respectively, $R$ is the gas constant, $\lambda$ is the molar volume ratio of the polymer to the drug, $\chi$ is the Flory-Huggins interaction parameter. $T$ is the temperature at which the measurement is made and $\nu_{\text{drug}}$ is the volume fraction of the drug in the polymer.

However, as the majority of pharmaceutically relevant drugs and polymers are solid, measuring the equilibrium solubility at room temperature is unfeasible. Therefore, several differential scanning calorimetry (DSC) protocols have been proposed based on determination of equilibrium thermodynamics at elevated temperature [1]. In a recently proposed protocol, referred to as the recrystallization method, a supersaturated amorphous solid dispersion is annealed at different temperatures above its glass transition temperature ($T_g$) to recrystallize excess drug and reach equilibrium solubility. The solubility after annealing is then derived from the $T_g$ of the annealed material using the Gordon-Taylor equation and extrapolated using the Flory-Huggins model to predict the solubility at room temperature [2]. Other noteworthy approaches include the melting point depression method [3] and an estimation based on the solubility in a liquid low molecular weight analogue of the polymer [4].

Introducing a confidence assessment

In order to assess the confidence of a prediction it is important to realize which variable is subject to experimental noise. Using the recrystallization method, the temperature ($T$) is the variable under control and can be regarded as free of error whereas the volume fraction of the drug ($\nu_{\text{drug}}$) is subject to error. The optimal estimate for the Flory-Huggins interaction parameter ($\chi$) is thus found by minimizing the sum of squares of the residuals between the observed and predicted $\nu_{\text{drug}}$. Consequently, the confidence of the prediction is expressed as a 95% prediction interval that is dependent on both the inter-replicate variance (reproducibility) and intra-replicate variance (fit to the Flory-Huggins model) [1].

Refining the experimental protocol

The introduction of a formal statistical analysis method enables a comparison of different solubility predictions. In the original method, a milling procedure was used to prepare the supersaturated amorphous solid dispersion [2]. However, as the physical properties and recrystallization behavior of an amorphous material have been reported to be affected by the preparation technique [5], the influence of different preparation techniques (ball milling, spray drying and film casting) on the solubility prediction was investigated [6].

As can be seen in Figure 1, the predicted solubility from the ball milling method is not consistent with those predicted from spray drying and film casting methods, indicating fundamental differences between the three preparation techniques. The most narrow prediction interval was found for spray drying, indicating a combination of a good fit to the Flory-Huggins model and reproducibility of the measurements. The prediction interval for ball milling was wider than that for spray drying, but still relatively narrow. However, as ball milling provided the best reproducibility of the three techniques, the broader prediction interval was a result of a poor fit to the model. In contrast, the broad prediction interval for film casting was a consequence of a poorer reproducibility than for the other two techniques. As previous studies suggest that amorphous mixtures produced by ball milling may still be heterogeneous at the molecular level, the process involved in reaching the equilibrium solubility is most likely driven by dissolution rather than the intentional recrystallization. Therefore, it is recommended that techniques such as spray drying or potentially film casting should be used to prepare the supersaturated amorphous solid dispersions when using this method [6].

Figure 1: Equilibrium solubility of IMC ($\chi_{\text{IMC}}$) in PVP K12 as a function of annealing temperature (Ta). Green diamonds (♦) represent the data from ball milling (a), red circles (●) represents the data from spray drying (b), and blue squares (■) represents the data from film casting (c). The data previously reported by Mahieu et al. (2013) is presented as black crosses (x). The evolution of solubility of the three data sets has been fitted with the Flory-Huggins model (black curves) including the 95% prediction interval (dotted curves). The grey circles (●) represent the experimental relationship between $T_g$ and $\chi_{\text{IMC}}$ and the grey curve is the Gordon-Taylor relationship.

Influence of polymer molecular weight on the prediction

One of the most commonly used carriers for amorphous solid dispersions is polyvinylpyrrolidone (PVP). However, despite the widespread use of PVP, the influence of polymer molecular weight (chain length) on drug-polymer solubility has not been sufficiently elucidated. Only a few studies have addressed this issue and none have supported the theoretical considerations and predictions with relevant experimental data [4]. Therefore, the influence of polymer molecular weight on the predicted solubility using spray drying as preparation technique was investigated [7].

As can be seen from Figure 2, it was found that the predicted solubility was independent of the molecular weight of the polymer. This indicates that the solubility of a given drug-polymer system is determined by the strength of the drug-polymer interactions rather than the molecular weight of the polymer. Therefore, during the initial screenings for drug solubility, only one representative molecular weight per polymer is needed. However, it is important to emphasize that this does not mean that the influence of polymer molecular weight on other important factors such as dissolution rate, physical stability and crystallization inhibition should not be considered in the polymer selection process [7].

Figure 2: Equilibrium solubility of IMC (XIMC) in PVP of different molecular weight as a function of annealing temperature ($T_a$). Red circles (●) represent the data from PVP K12, green squares (■) represent the data from PVP K25, blue diamonds (♦) represent the data from PVP K30, and purple triangles (▲) represent the data for PVP K90. The evolution of solubility of the four data sets has been fitted with the Flory-Huggins model (black curves) including the 95% prediction interval (dotted curves). The grey circles (●) represent the experimental relationship between $T_g$ and $\chi_{\text{IMC}}$ and the grey curve is the Gordon-Taylor relationship.

Conclusions

Knowledge about drug-polymer solubility is an important factor in the development of amorphous solid dispersions as it can ensure the thermodynamic stability of the formulation. Previously, the prediction of drug-polymer solubility was based on a central estimate without an assessment of the confidence of the prediction. By introducing a new dimension to the field in form of formal statistical analysis, we enabled the possibility of comparing different solubility predictions. This can be used advantageously to screen for polymers suitable for amorphous solid dispersions.

Author affiliations

Matthias Manne Knopp and Rene Holm are affiliated with the Department of Pharmaceutical Science and CMC Biologics at H. Lundbeck A/S and Thomas Rades is a Professor in the Department of Pharmacy at the University of Copenhagen. All work has been conducted at H. Lundbeck A/S.

PSSRC Facilities

The research group of Prof. Thomas Rades in Copenhagen focusses on the development of amorphous solid dosage forms including amorphous solid dispersions and co-amorphous formulations. Several methods can be applied to obtain the amorphous form and therefore, the group has extensive knowledge and experience in techniques such as ball milling, spray drying and melt-quenching. In order to assess the stability and physicochemical properties of the formulations, the facilities include XRPD, a range of spectroscopic and microscopic techniques, and state of the art thermal analysis equipment including the DSC, TGA, DMA, and IMC.

Background

Solid dispersions are an intensively investigated enabling technology to formulate poorly soluble drugs. Many contributions already studied their higher solubility and resulting dissolution rate as well as the challenges at the level of physical stability due to their high intrinsic energy. Whereas the vast majority of these studies focus on the bulk characteristics of the samples, we are convinced that the (often distinct) properties of the sample surface should not be overlooked.

In this research highlight, we invigorate our statement by illustrating the surface characterization of a spray-dried polymeric matrix consisting of a combination of PLGA and PVP. In a later stage this matrix will be used to process poorly soluble drugs as a solid dispersion. The study of the sample surface was motivated by the fact that the spray-dried particles are hollow microspheres with a relatively thin shell, which implies that their surface comprises a significant part of the total sample mass [1]. Hence a change in surface characteristics (for example due to exposure to heat and/or humidity) will significantly alter the performance of these samples. Furthermore the microparticle surface will always be the first part of the formulation to come into contact with its release environment. Thus, surface characteristics might significantly influence the behaviour of the formulation, both in terms of release characteristics and stability issues.

Nanoscale surface characterization and miscibility study

Microparticles consisting of two polymers, PLGA and PVP, were prepared by spray drying. The phase behaviour of the samples was studied by means of modulated differential scanning calorimetry (MDSC) and the results showed that phase separation occurred in the bulk sample through evidence of two mixed amorphous phases, namely, a PLGA-rich phase and a PVP-rich phase (Figure 1a). Characterization of the samples by scanning electron microscopy (SEM) demonstrated that the spray-dried particles were hollow with a thin shell (Figure 2). Because of the importance in relation to stability and drug release, information about the surface of the microparticles was collected by different complementary surface analysis techniques. Atomic force microscopy (AFM) gathered information about the morphology and phase behaviour of the microparticle surface. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) analysis of the particles revealed that the surface consisted mainly of the PLGA-rich phase. This information was obtained by C60+ sputtering, a technique allowing the collection of data with an increasing distance from the surface (Figure 3). This was confirmed by X-ray photoelectron spectroscopy (XPS) at an increased sampling depth (10 nm). Nanothermal analysis (NanoTA) proved to be an innovative way to thermally detect the presence of the PLGA-dominated surface layer and the underlying PVP phase (Figure 4) [1].

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Influence of heat and humidity on the sample surface

The first part of this study focused on the influence of exposure to heat upon the phase behaviour of the spay-dried polymeric matrix both at the bulk level (investigated by MDSC) and at the surface level (examined by ToF-SIMS, XPS and AFM).

MDSC results demonstrated that exposure of the sample to heat influenced the Tg of the spray-dried polymeric matrix in terms of its value (Figure 1b) as well as the width of the Tg region (Figure 1c). Thus, MDSC showed a change in the bulk miscibility and hence phase behaviour of the spray-dried microspheres.

In addition, surface analysis revealed an undeniable influence of heat upon the surface characteristics of the polymeric microspheres, and more specifically upon their chemical composition, phase behaviour and topography. The conclusion from all techniques used (ToF-SIMS (Figure 5), XPS and AFM (Figure 6)) was that exposure of the spray-dried polymeric matrix to elevated temperatures resulted in a surface rearrangement with the appearance of spots of the underlying PVP layer at the PLGA surface. The overall result is an augmented surface coverage of PVP combined with a lower PLGA coverage.

The observations for exposing the microspheres to humidity were similar to those for exposure of the samples to heat The appearance of the underlying PVP layer at the PLGA surface of the microspheres is proposed to be mainly caused by the increased molecular mobility of the PLGA surface layer, to a lesser extent combined with the swelling behaviour of PVP upon exposure to humidity or heat [2].

This study implies that exposure to elevated temperatures and humidity might influence the bulk miscibility and release behaviour of future drug formulations based on this matrix.

Outlook

In a next phase a poorly soluble API will be included in this polymeric matrix as a solid dispersion. The influence of different formulation and process parameters on the surface coverage and spatial distribution of the API in the microspheres will be investigated. Moreover the consequences of differences in API spatial distribution and surface coverage on the release behaviour of the formulation will be studied. An understanding of the surface behaviour will form the basis for the rational development of a drug matrix with desired and tunable characteristics in terms of drug solubility enhancement and drug release profile.

PSSRC Facilities

The Research group of Prof. Guy Van den Mooter focuses on the study of the physical chemistry of solid (molecular) dispersions prepared by hot melt extrusion, spray drying, bead coating and spray congealing. It is the aim to correlate the physical structure of the drug-polymer dispersions to their pharmaceutical performance and stability profile, and to correlate formulation and processing parameters to the resulting physical structure. Analytical techniques such as thermal analysis (DSC, MTDSC, TGA, hot-stage microscopy, isothermal microcalorimetry, solution calorimetry), X-ray powder diffraction, infrared spectroscopy, solid state NMR and in vitro (intrinsic) dissolution testing are being used for this purpose. Other (solid state) analytical techniques that are available are (powder) rheology, He-pycnometry, instrumented compression testing, SEM, TEM, coulter counter and Laser diffraction.

Background

The structural and physical stability of solid dispersions have not been adequately explored during post spray drying manufacturing processes. Solid dispersions are preferentially formulated as solid dosage forms such as tablets and capsules. Formulation parameters of spray drying may lead to differences in physical form and amorphous content of solids in single component systems [1]. However, there is limited understanding on the effect of spray drying processes and formulation variables on drug-polymer mixing in solid dispersions and this limitation also extends to the unit operations such as milling and tabletting. The drug-polymer mixing in solid dispersions was evaluated in two different laboratory spray dryers, the Buchi-mini spray dryer and Pro-C-epT Micro spray dryer (Figure 1). The effect of compression on the structural and the physical stability of the spray dried solid dispersions was investigated as a major scope of this study.

Drug-polymer mixing of solid dispersions across the spray dryers

The solid dispersions with 30% drug loading prepared by Pro-C-epT Micro spray dryer showed significant differences (p <0.05) in Tg width between transport tube/cooling tube and cyclone/collector (Figure 2). The solid dispersions from the transport tube showed the narrowest Tg width which is also far below the Tg width of the pure polymer followed by that of the cooling tube, the collector and the cyclone. The samples from the transport tube and cooling tube showed better drug-polymer mixing than the solid dispersions from the collector and the cyclone.

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The solid dispersion of 50 % (w/w) NAP in PVP-VA collected from the cyclone tube connected to the drying chambers (CYTU) was amorphous. Powders collected from the cyclone and the CSP were crystalline solid dispersions which showed a melting endotherm (Tm) at 111.21 ± 0.08 °C and 112.68 ± 0.15 °C, respectively (Figure 3).

The drug-polymer mixing and the solid forms can vary across the spray dryer and high drug loading solid dispersions may be more prone to variation due to their lesser stability.

Effect of compression on structural and physical stability of the solid dispersions

Solid dispersions from CSP of Buchi mini-spray dryer and COLL of Pro-C-epT Micro-spray dryer were used for the compression study. The halo pattern of the uncompressed samples, both in the case of Buchi mini-spray dryer and Pro-C-epT Micro-spray dryer, showed higher intensity at 2θ=16.11 halo maximum than the compressed amorphous solid dispersions. The differences in the halo pattern apparently indicate the structural dissimilarity and also the differences in the short range order in the solid dispersion (Figure 4).

The vibration band of the amide carbonyl of PVP-VA becomes broader after compression due to an increase in the intensity of the shoulder peak of the weak drug-polymer interaction at 1654 cm-1 (Figure 5). The spectroscopic study evidently showed that compression of 30% (w/w) NAP in PVP-VA solid dispersion enhanced the weak drug-polymer interaction.

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After 21 days storage at ambient temperature and 75% RH, the Tg width became broader for the uncompressed solid dispersions with 30% (w/w) NAP in PVP-VA 64 compared to the compressed samples (p<0.05) (Figure 6). The homogeneity of the compressed samples seems intact and also slightly decreased which could be the result of enhancement of the weak drug-polymer interaction.

After 10 days of storage the melting enthalpy and the crystallinity of the uncompressed sample with 50% drug loading were much higher (about two fold) than the compressed sample due to slower crystallisation of naproxen from the amorphous domain of the compressed samples (Figure 7). After five months storage at high humidity (75% RH) and ambient temperature, the Bragg peaks intensity was higher for the uncompressed solid dispersions with 40% and 50% drug loading than the compressed at 188 MPa (Figure 8). The lower crystallinity of the compressed samples can be related to the improved drug-polymer interactions.

Surface crystallisation is a common phenomenon for amorphous drugs [2, 3]. The decrease in effective surface area due to compression probably diminished the crystallisation of naproxen in the solid dispersions.

Outlook

The drug-polymer mixing for solid dispersions varies across the spray dryer. Compression clearly improved drug-polymer interactions and further manifested as lesser crystallinity compared to the uncompressed solid dispersions. The Tg width and the PXRD halo patterns can also be used in combination with vibrational spectroscopic techniques to predict the drug-polymer mixing and the physical stability of the solid dispersions.

Future Work

The sources of drug-polymer mixing variations across a spray dryer and their impact on drug product performance apparently need dedicated further investigation. Further studies on the effect of compression on the structural and physical stability of solid dispersions are ongoing using pharmaceutical relevant dwell times and compression pressures.

PSSRC Facilities

The Research group of Prof. Guy Van den Mooter focuses on the study of the physical chemistry of solid (molecular) dispersions prepared by hot melt extrusion, spray drying, bead coating and spray congealing. It is the aim to correlate the physical structure of the drug-polymer dispersions to their pharmaceutical performance and stability profile, and to correlate formulation and processing parameters to the resulting physical structure. Analytical techniques such as thermal analysis (DSC, MTDSC, TGA, hot-stage microscopy, isothermal microcalorimetry, solution calorimetry), X-ray powder diffraction, infrared spectroscopy, solid state NMR and in vitro (intrinsic) dissolution testing are being used for this purpose. Other (solid state) analytical techniques that are available are (powder) rheology, He-pycnometry, instrumented compression testing, SEM, TEM, coulter counter and Laser diffraction.

Non-linear Optical Imaging

Non-linear optical imaging is an emerging technique for imaging drugs and dosage forms [1]. Non-linear optical imaging may be used for non-destructive, non-contact imaging of solid drugs and dosage forms. It offers chemical and structural specificity with no requirement for labels, sub-micron spatial resolution (inherent confocal nature), rapid video-rate image acquisition, and the ability to image samples in aqueous environments in situ.

These combined features make non-linear optical imaging unique compared to existing imaging approaches in the pharmaceutical setting and make the technique well suited to a wide range of solid-state formulation and drug delivery analyses. These include imaging chemical and solid-state form distributions in dosage forms, drug release and dosage form digestion, and drug and micro/nanoparticle distribution in tissues and within live cells. While non-linear optical imaging is comparatively well established in the biomedical field, pharmaceutical applications of non-linear optical imaging are much less widely explored.

Principle of Non-linear Optical Imaging

Non-linear optical imaging involves irradiation of a sample with laser light (at one or two wavelengths) through an optical microscope and detection of scattered light at a different frequency. Non-linear optical imaging is also sometimes referred to as multi-photon imaging since the non-linear processes involve several photons (Figure 1). The technique encompasses a range of non-linear optical phenomena including second harmonic generation (SHG), coherent anti-Stokes Raman scattering (CARS) and two-photon fluorescence (TPF). In SHG, the energy of two photons is combined to emit light at half the laser wavelength. This process depends on the structural symmetry of the sample, and can be used to resolve crystalline and amorphous materials and some different polymorphic forms. In CARS, three photons at two or three wavelengths interact to efficiently generate light at a shorter wavelength (anti-Stokes Raman scattering). The technique is related to normal (spontaneous) Raman imaging, and is also used for label-free chemically-selective imaging. However CARS imaging is orders of magnitude faster, the spatial resolution is usually better and interference from fluorescence may be avoided. TPF is related to normal (one-photon) fluorescence, but it involves the energy of two incident photons instead of one with the advantage of being inherently confocal. Some materials (e.g. indomethacin, doxorubicin) generate TPF and so can be imaged with this technique without the requirement for labels. Vibrational energy level diagrams representing the SHG, CARS and TPF processes are shown in Figure 1.

Since the non-linear optical phenomena have different advantages and specificities, it is often very helpful to collect a combination of these signals at the same time with the same imaging setup. This is known as "multi-modal" imaging.

Imaging Solid Drugs and Dosage Forms

It is becoming widely recognised that critical solid dosage form properties, such as drug dissolution and release, are dependent not only on the formulation composition but also the component and solid state form distribution. Non-linear optical imaging is well suited to imaging a range of dosage forms. It is capable of rapidly imaging different chemical components and solid forms with high resolution (micron or sub-micron) in three dimensions. In general the data for the images may be collected in a few seconds or less. The technique may also be used to image changes in dosage forms in situ during drug release/dissolution and storage [2].

Distributions of components in tablets may be imaged in 2D or 3D, as shown in Figures 2 and 3. Both drug and excipient distributions may be imaged.

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Future Work

As mentioned above, the technique is suited for real time imaging of drug release/dissolution. In collaboration with the Optical Sciences Group, University of Twente, The Netherlands and Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Duesseldorf, Germany we are currently working on imaging drug and dosage form changes in a flow-through cell while simultaneously analysing drug concentration in solution.

Non-linear optical imaging is also well suited to real-time imaging of cells and tissues. We are currently working on imaging delivery of poorly water soluble drugs in various types of formulations in vitro and in vivo. If feasible, this approach will facilitate bringing together the analysis of drug release/dissolution and permeability, and should help lead to better understanding of absorption of these drugs.

PSSRC Facilities

Asst. Prof. Clare Strachan (Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki) has several years' experience in non-linear optical imaging of a range of solid dosage forms. A fully integrated commercial non-linear optical microscope (Leica TCS SP8 CARS microscope) is available at the University of Helsinki. This is the first commercially available fully integrated CARS microscope in the world. The microscope uses a picosecond solid-state-laser light source to excite single Raman lines within a range of 1250 cm-1 to 3200 cm-1 for CARS imaging. It gives access to molecular specific contrast based on a variety of Raman-active vibrations relevant to pharmaceutical applications. Second harmonic generation (SHG) and two-photon fluorescence (TPF) are also possible with the setup. The microscope is also capable of one-photon fluorescent imaging in the UV and visible wavelengths. All non-linear and fluorescence phenomena can be imaged on exactly the same sample with the same microscope, and therefore a direct comparison of the imaging approaches can be made.

Formulation of co-amorphous drug systems

Using the amorphous form of a drug, instead of its crystalline counterpart is one way to enhance the bioavailability of poorly water-soluble drugs. However, in order to fully benefit from the solubility advantages of amorphous drugs, one needs to overcome phyisco-chemical limitations including poor physical stability associated with the amorphous form. Co-amorphous drug formulations are a novel and one of the most promising formulation approaches in this context, where the drug in its amorphous form is stabilized through strong intermolecular interactions with its co-amorphous low molecular weight partner molecule.

Background and Formulation Strategy

The formulation of a poorly water-soluble crystalline drug into its high energy amorphous form has been shown to be a promising approach to increase dissolution properties and thus bioavailability. However, due to their high internal energy, pure amorphous drugs often show fast recrystallization kinetics to the low energy (low solubility) crystalline state. Thus, the applicability of amorphous drugs is usually limited by their poor physical stability [1].

A high glass transition temperature (Tg) is often connected with improved physical stability of amorphous compounds. Below the Tg molecular movement is drastically reduced which lowers the chance of molecular reorientation and therefore, crystal nuclei formation and crystal growth [2]. Increasing the Tg by incorporation of the drug into polymers was the main idea behind solid dispersions or glass solutions. This is a sensible and promising approach, but so far has only lead to very few marketed products, which can be attributed to problems associated with solid dispersions such as limited solubility of the drug in the polymer or hygroscopicty of the polymers [3].

The idea behind the co-amorphous formulation approach is to stabilize the amorphous form of a drug by strong and specific molecular interactions between the drug and a low molecular weight partner molecule. These interactions, rather than merely a high Tg, will prevent the drug from recrystallization and thus ensure physical stability. For the drug to recrystallize, first the interactions need to be broken, second the molecules need to reorientate in the co-amorphous mixture and third like molecules need to meet and form a crystal nuclei.

Drug-Drug combinations

Co-amorphous drug-drug formulations were introduced by Chieng et al. (2009) as new delivery systems for poorly water-soluble drugs that are suitable for combination therapy, i.e. with similar doses and pharmacological profile. The feasibility of this approach has been shown for several drug-drug combinations [5]. These initial studies concentrated on the basic solid-state characterization, molecular interactions, recrystallization and dissolution improvement.

The main research outcome was to establish the importance of molecular interactions in the physical stability of amorphous formulations. It could be shown that recrystallization is mainly driven by the absence of intermolecular interactions rather than a high Tg.These interactions are crucial for the physical stability of co-amorphous systems [4, 6, 7]. For example, specific interactions between the drugs indomethacin and naproxen resulted in the formation of a drug heterodimer in the co-amorphous blend [8]. For the drugs to recrystallize this heterodimer needed to disassociate and the molecules needed to reorientate themselves towards homodimers, which are then able to create a crystal nuclei (Figure 1).

The dissolution of the co-amorphous formulations was increased not only over the pure crystalline drugs but also over the pure amorphous drugs. The interacting nature in co-amorphous drug-drug mixtures furthermore resulted in a synchronized release, i.e. both drug molecules are dissolved in a pair wise fashion at a similar rate [6, 7]. It was also possible to show that plain molecular level mixing itself has a positive effect on the physical stability of co-amorphous formulations [9].

Drug-amino acid formulations

The co-amorphous formulation approach was further developed by Löbmann et al. (2013), introducing amino acids as low molecular excipients for these systems (Figure 3) [10, 11]. The need for suitable low molecular weight excipients was pressing, firstly to enable the formulation of co-amorphous single drug delivery systems and secondly to be able to compete with other amorphous formulation approaches, i.e. solid dispersions.

It was possible to produce highly stable co-amorphous drug-amino acid combinations with enhanced dissolution kinetics. The formulations showed strong intermolecular interactions between the drugs and the amino acids, and had markedly higher Tgs than the pure drug. Due to the low molecular weight of the amino acids, the total amount of “excipients” in these formulations was also rather low. Furthermore, amino acids can be regarded as generally safe because they are part of the daily nutrition. The co-amorphous drug-amino acid formulation approach may be regarded as an attractive alternative to the use of polymer based solid dispersions.

Outlook

We have demonstrated the huge potential of the co-amorphous formulation approach. This a completely new strategy in stabilizing the amorphous form of a drug and gives interesting and alternative opportunities for formulating poorly water soluble drugs into amorphous dosage forms. We are confident to further establish this formulation strategyfor poorly water soluble drugs into a competitive platform technology.

PSSRC Facilities

The group of Prof. Thomas Rades in Copenhagen has extensive experience in formulation, drug delivery and physical characterization of solid drugs and dosage forms. In particular, research has focused on in depth characterization of amorphous forms of drugs, new analytical techniques for the investigation of solids, and the development of new concepts for the stabilization of amorphous systems.